Hyperglycemia, hypertriglyceridemia and hyperinsulinemia are key clinical features of patients presenting with metabolic disorders and/or non-insulin-dependent diabetes mellitus (NIDDM). Following maximal insulin secretion by the pancreas to regulate rising glucose and triglyceride levels, higher glucose and triglyceride levels cannot be regulated by the circulating high levels of insulin, resulting in “insulin resistance” in patients with diabetes and metabolic disorders. In pre-diabetic conditions, patients have moderate levels of hyperglycemia and hypertriglyceridemia associated with moderate hyperinsulinemia. If there are better therapeutic agents available to regulate glucose and triglyceride levels when the patients do not have advanced disease, there will be a big therapeutic and pharmacoeconomic benefit from management of such patients before they become “insulin resistant”.
Nordihydroguiaretic Acid (“NDGA”) is a bisphenolic compound that occurs naturally in the leaves and small stems of the creosote bush, Larrea divaricata. It was first isolated by Walter, et al., in 1945 (J. Amer. Pharm. Assoc. Sci., 34:78-81.) Its use in traditional medicine was widespread in the 20th century, and included the treatment of diabetes, kidney problems, urinary tract infections, rheumatism, arthritis, wounds, skin injuries and paralysis (Winkelman, et al., J. Ethnopharm. 18:109-131 (1986).)
NDGA has been shown to enhance glucose disposition and inhibit lipolysis (Gowri, M. S. et al., Metabolism: Clinical and Experimental, 48(4): 411-414 (1999).) As demonstrated using isolated rat adipocytes, NDGA has a profound effect on glucose and lipid metabolism at the cellular level, which involves at least in part its ability to optimize insulin sensitivity of glucose and lipids.
Effective oral delivery of small molecule therapeutic agents is complicated by the insolubility of the agent. Like many other phenolic small molecule therapeutics, NDGA is insoluble in aqueous media, but is soluble in organic solvents such as methanol and ethanol. Attempts have been made to increase its solubility in water by derivatizing the molecule. For example, U.S. Patent Application No. 2009/0306070 describes a tetra-O-substituted butane bridge modified form of NDGA with enhanced water solubility. In U.S. Patent Application 2010/0022528, solubility is enhanced by forming tetra-substituted NDGA derivatives vie ether bonds and/or carbamate bonds. Another approach is described in Bioorganic and Medical Chemistry Letters, 18(6):1884-1888 (2008), wherein NDGA is derivatized into its corresponding phenol ether, carbamate or carbonate.
Although the use of a more water soluble form of NDGA for oral delivery may enhance absorption overall, this approach alone does not address the problems associated with attempts to enhance efficacy by tailoring absorption kinetics and physiological delivery profiles for specific purposes. More specifically, “immediate” release formulations of NDGA will not allow optimal pharmacokinetic profiles of NDGA to provide adequate regulation of increased glucose and triglyceride levels.
Accordingly, there is a need to enhance efficacy of orally administered NDGA formulations to optimize absorption kinetics, slowing elimination, improving physiological delivery profiles, reducing total NDGA dose levels and dosing frequency, and overall better therapeutic management of hyperglycemia and hypertriglyceridemia which is observed in patients with early as well as advanced stages of diabetes and/or metabolic disorders. As described herein, such formulations involve the use of multimodal release dosage forms of NDGA. Examples of such formulations include bimodal oral release dosage forms, which incorporate slow- and sustained-release oral dose delivery systems, to allow pharmacologically optimal oral delivery of NDGA.